Ignite Creation Date:
2024-05-06 @ 7:55 AM
Last Modification Date:
2024-10-26 @ 11:53 AM
Study NCT ID:
NCT02626507
Status:
UNKNOWN
Last Update Posted:
2022-02-09
First Post:
2015-12-07
Brief Title:
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ERHER2- Breast Cancer
Sponsor:
Hoffman Oncology
Organization:
Hoffman Oncology
Study Overview
Official Title:
Phase I Dose-Escalation Study of Combination of Gedatolisib a Dual Inhibitor of PI3-K and mTOR With Palbociclib and Faslodex in the Neoadjuvant Setting in Previously Untreated Patients With ERHER2- Breast Cancer
Status:
UNKNOWN
Status Verified Date:
2022-01
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a dose-escalation Phase Ib clinical trial in 18 patients with newly diagnosed Stage I-IV ERHER2- breast cancer with the primary cancer in place These patients have not received prior therapy for their breast cancer and intend to undergo surgery after four cycles of therapy
This is an open-label study and investigators and subjects are not blinded to the treatment The reason for using an open-label study design is because this is a dose-escalation trial and the investigators need to determine the potential toxicity before a decision can be made to continue the dose escalation procedures
The assignment of patients will not be randomized as this is a dose-escalation trial
This is an open-label study and investigators and subjects are not blinded to the treatment The reason for using an open-label study design is because this is a dose-escalation trial and the investigators need to determine the potential toxicity before a decision can be made to continue the dose escalation procedures
The assignment of patients will not be randomized as this is a dose-escalation trial
Detailed Description:
Palbociclib Ibrance is an orally active highly selective reversible inhibitor of cyclin-dependent kinase CDK 4 and CDK 6 Faslodex Fulvestrant is a potent anti-estrogen drug that binds and degrades estrogen receptors ERs Interim results from the Phase 3 trial Study PALOMA-3 have shown that combination of palbociclib and Faslodex increases progressive-free survival PFS from 38 to 92 months in patients with metastatic estrogen receptor positive ER and human epidermal growth factor receptor 2 negative HER2- breast cancer that progressed during or after anti-endocrine therapy Turner et al 2015 The palbociclibFaslodex combination was found to be well tolerated Additionally there is growing data indicating that this combination can be safely and effectively administered up front in anti-endocrine therapy-naive patients in the neoadjuvant setting
Gedatolisib code name PF-05212384 formerly known as PKI-587 is an intravenous IV adenosine triphosphate ATP competitive highly selective and potent inhibitor of pan-class I isoform phosphatidylinositol-45-bisphosphate 3-kinase PI3-K and mammalian target of rapamycin mTOR Fry et al 2004 Preclinical and first-in-human studies have shown a manageable safety profile with predictable toxicity for this class of drugs
Activation of the PI3-KAktmTORp-S6 pathway has been associated with endocrine resistance in ER breast cancer There is ample evidence that inhibition of this pathway in combination with anti-hormonal therapy increases PFS Baselga et al 2012 There is also clinical evidence that combination therapy targeting all three pathways is feasible safe and effective Sweeney et al 2014 The advantage of Gedatolisib is its potential to inhibit signaling through different PI3-K isoforms Also important is the fact that once a week administration may be as effective but less toxic than chronic oral dosing If hyperglycemia is a surrogate for effective PI3-KAktmTORp-S6 inhibition once weekly dosing of Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as chronically oral dosing and with less toxicity
Preoperative or neoadjuvant systemic chemotherapy once reserved for patients with locally advanced breast cancer in whom the goal was to render large breast cancers operable has become increasingly common due to the improvement in disease-free survival and overall survival Historically the endpoint of pathological Complete Response pCR in neoadjuvant therapy against ERHER2- breast cancer has been of limited value However new targeted agents with higher response rates have the potential to use pCR assessment as a strong clinical endpoint in drug development Given the systemic response rate in previously treated Stage 4 breast cancer patients the expectation will be a similar high rate of pathological improvement which can lead to greater use of targeted agents in the neoadjuvant setting
In addition to the potential of better pathological improvement the advantage of clinical studies involving neoadjuvant therapy is that they can provide response information in patients that are treatment-naïve This type of clinical trial can also be used to assess cellular and molecular changes with serial biopsies while on neoadjuvant therapy which can aid in development of companion tissue andor imaging biomarkers and further the development of preclinical models
Accordingly this investigation assesses the safety and efficacy of the combination of Gedatolisib palbociclib and faslodex in the neoadjuvant setting in previously untreated patients with ERHER2- breast cancer Being the first clinical trial using this combination in neoadjuvant setting one of the main objectives for the current trial is to determine the Maximum Tolerated Dose MTD of Gedatolisib when used in combination with palbociclib and faslodex Subsequent Phase II clinical trials will be conducted to assess the safety and efficacy of the Gedatolisibpalbociclibfaslodex combination with the dose of Gedatolisib being the MTD determined from the current trial
Gedatolisib code name PF-05212384 formerly known as PKI-587 is an intravenous IV adenosine triphosphate ATP competitive highly selective and potent inhibitor of pan-class I isoform phosphatidylinositol-45-bisphosphate 3-kinase PI3-K and mammalian target of rapamycin mTOR Fry et al 2004 Preclinical and first-in-human studies have shown a manageable safety profile with predictable toxicity for this class of drugs
Activation of the PI3-KAktmTORp-S6 pathway has been associated with endocrine resistance in ER breast cancer There is ample evidence that inhibition of this pathway in combination with anti-hormonal therapy increases PFS Baselga et al 2012 There is also clinical evidence that combination therapy targeting all three pathways is feasible safe and effective Sweeney et al 2014 The advantage of Gedatolisib is its potential to inhibit signaling through different PI3-K isoforms Also important is the fact that once a week administration may be as effective but less toxic than chronic oral dosing If hyperglycemia is a surrogate for effective PI3-KAktmTORp-S6 inhibition once weekly dosing of Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as chronically oral dosing and with less toxicity
Preoperative or neoadjuvant systemic chemotherapy once reserved for patients with locally advanced breast cancer in whom the goal was to render large breast cancers operable has become increasingly common due to the improvement in disease-free survival and overall survival Historically the endpoint of pathological Complete Response pCR in neoadjuvant therapy against ERHER2- breast cancer has been of limited value However new targeted agents with higher response rates have the potential to use pCR assessment as a strong clinical endpoint in drug development Given the systemic response rate in previously treated Stage 4 breast cancer patients the expectation will be a similar high rate of pathological improvement which can lead to greater use of targeted agents in the neoadjuvant setting
In addition to the potential of better pathological improvement the advantage of clinical studies involving neoadjuvant therapy is that they can provide response information in patients that are treatment-naïve This type of clinical trial can also be used to assess cellular and molecular changes with serial biopsies while on neoadjuvant therapy which can aid in development of companion tissue andor imaging biomarkers and further the development of preclinical models
Accordingly this investigation assesses the safety and efficacy of the combination of Gedatolisib palbociclib and faslodex in the neoadjuvant setting in previously untreated patients with ERHER2- breast cancer Being the first clinical trial using this combination in neoadjuvant setting one of the main objectives for the current trial is to determine the Maximum Tolerated Dose MTD of Gedatolisib when used in combination with palbociclib and faslodex Subsequent Phase II clinical trials will be conducted to assess the safety and efficacy of the Gedatolisibpalbociclibfaslodex combination with the dose of Gedatolisib being the MTD determined from the current trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None